This proposal will enhance the PI's background in trial design and statistics and improve his mentoring skills. It allows time for mentoring fellows who will receive extensive training in statistics and trial design, in the clinical presentation MS, and in essential lab techniques to aid in investigation of immunological mechanisms in MS. Fellows are an integral part of all aspects of trial design, execution, and analysis of two investigator-initiated trials. The first trial determines if anti-VLA-4 antibodies will slow primary progressive MS-a form of MS refractory to all current therapy. Drug infusion, monitoring, and processing of blood for gene profiling will take place in the CRC. Therapeutic effects will be measured with a novel combination of measures including our MS-specific quality of life scale, cervical spinal cord MRI volume and magnetization transfer ratio, and neurophysiological function (motor evoked potentials and autonomic testing), plus neurological exams. A second, longitudinal trial extends our recent finding of defective interferon-beta signaling in lymphocytes of clinically active MS patients. We will determine if subnormal levels of an activated transcription factor in lymphocytes reflects disease state, predicts transition to progression, and marks responses to therapy. In parallel, we will determine the molecular basis of the IFN-beta signaling defect, whether it reflects a fundamental biological abnormality affecting clinical manifestations, and whether it can be reversed by drug therapy. Long-term goals for the PI are to develop and mentor skills in trial design and statistical analysis in order to craft investigator-initiated trials that examine basic mechanisms of disease and novel therapies. The PI will receive pharmacogenomics and proteomics training, an important part of future investigator-initiated trials of this complex disease. He will also expand and improve clinical fellowship training in MS in conjunction with the CRC, Dept. of Health Studies and its K30 program, and educate fellows in trial design, statistics, and all neurologic aspects of MS.